The general objective of this proposal is to develop a center for the study of abnormal carbohydrate metabolism based on experimental observations of developmental events in animals, established disease patterns in humans, its effect on the offspring, and the mechanisms leading to the diabetic state in both animals and humans. It is anticipated that this effort will provide a more rational therapy for diabetic patients. The specific objectives are: a) clarify the relationship between diabetes in women and the occurrence of congenital abnormalities in their offspring, b) provide the scientific knowlege necessary to reduce fetal morbidity and mortality resulting from ketosis in pregnancy, c) study the role of newly recognized hormones in the regulation of carbohydrate metabolism during development in rats, d) determine the mechanisms operative in regulation of carbohydrate metabolism during extra-uterine adaptation to infants, e) study the mechanisms leading to hyperinsulinemia and its effects on hormonal hepatic clearance, hepatic ketogenesis and glycogenolysis in the genetically obese rodent, f) develop an external programmable microelectronic control system for insulin administration in the control of diabetes mellitus in humans after appropriate observations in diabetic dogs with an implantable pump and reservoir system exploring the feasibility of intraperitoneal versus intravenous insulin therapy, and g) clarify the relationship between binding of insulin and its degradation and the factors that regulate its metabolic disposition. It is hoped that careful examination of events in a systematic approach to human and animal experimentation relating to diabetes mellitus will be of considerable help both in understanding and modifying the present outlook of diabetes.